Red blood cells
Researchers say they have discovered a genetic mutation that triggers erythropoietic protoporphyria (EPP).
The team performed genetic sequencing on members of a family from Northern France who had EPP of a previously unknown genetic signature.
The sequencing revealed a mutation in the gene CLPX that promotes EPP.
Barry Paw MD, PhD, of the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in Massachusetts, and his colleagues reported this discovery in PNAS.
About EPP
To produce heme, the body goes through porphyrin synthesis, which mainly occurs in the liver and bone marrow. Genetic defects can hinder the body’s ability to produce heme, and a decrease in heme production leads to a buildup of protoporphyrin components.
In the case of EPP, protoporphyrin IX accumulates in the red blood cells, plasma, and sometimes the liver.
When protoporphyrin IX is exposed to light, it produces chemicals that damage surrounding cells. As a result, people with EPP experience swelling, burning, and redness of the skin after exposure to sunlight.
“People with EPP are chronically anemic, which makes them feel very tired and look very pale, with increased photosensitivity because they can’t come out in the daylight,” Dr Paw said. “Even on a cloudy day, there’s enough ultraviolet light to cause blistering and disfigurement of the exposed body parts, ears, and nose.”
Although some genetic pathways leading to the build-up of protoporphyrin IX have already been described, many cases of EPP remain unexplained.
New discovery
Dr Paw and his colleagues noted that heme synthesis is controlled by the mitochondrial AAA+ unfoldase ClpX, which participates in the degradation and activation of δ-aminolevulinate synthase (ALAS).
In their analysis of the French family with EPP, the researchers discovered a dominant mutation in the ATPase active site of CLPX. This mutation—p.Gly298Asp—prompts the accumulation of protoporphyrin IX.
The researchers said the mutation partially inactivates CLPX, which increases the post-translational stability of ALAS. This increases ALAS protein and ALA levels and leads to the accumulation of protoporphyrin IX.
“This newly discovered mutation really highlights the complex genetic network that underpins heme metabolism,” Dr Paw said. “Loss-of-function mutations in any number of genes that are part of this network can result in devastating, disfiguring disorders.”
Dr Paw also noted that identifying the mutations that contribute to EPP and other porphyrias could pave the way for new methods of treating these disorders.
